Pyrimidine compounds and use thereof

Abstract

The invention relates to pyrimidine compounds of general formula (I), and to the use of these compounds of general formula (I) and of the physiologically compatible acid addition salts of compounds (I) for producing a pharmaceutical agent for treating diseases, which respond to the influence of dopamine D 3 receptor antagonists or agonists.

1. A compound of the formula I 
       
         
           
           
               
               
           
         
       
       in which
 A is a C═W or CR f R g  group; 
 B is a chemical bond or a CR h R i  group; 
 X is O, S, an N—R k  group or a CR m R n  group; 
 D is CO═O or a chemical bond; 
 E is a linear or branched 2 to 10 membered alkylene chain which may have as chain members 1 or 2 non-adjacent heteroatomic groups(s) K which is selected from O, S, S(O), S(O) 2  and N—R p , and which may comprise a carbonyl group and/or a cycloalkanediyl group and/or may have a double or triple bond; 
 W is oxygen or sulfur; 
 Z forms together with the C atoms to which it is bonded a fused 5-, 6- or 7-membered carbocycle or heterocycle which has 1, 2, 3, or 4 heteroatoms which are selected from N, O, and S, where the fused carbocycle and the fused heterocycle may have 1 or 2 carbonyl groups as ring members and/or 1, 2, 3, or 4 substituents R which are selected from optionally substituted C 1 -C 6 -alkyl, CN, OR 1 , NR 2 R 3 , NO 2 , SR 4 , SO 2 R 4 , SO 2 NR 2 R 3 , CONR 2 R 3 , COOR 5 , COR 6 , C 1 -C 4 -haloalkoxy, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, C 2 -C 6 -alkenyloxy, C 2 -C 6 -alkynyloxy, C 3 -C 6 -cycloalkyl, C 3 -C 6 -cycloalkyloxy and halogen and/or 2 substituents R may together form a chain X′-Alk′-X″ in which X′ and X″ are independently of one another O or S, and Alk′ is C 1 -C 4 -alkanediyl which optionally has 1, 2, 3, or 4 alkyl groups or halogen atoms as substituents; 
 J is CH 2 —CH 2 ; 
 M is N; 
 Y is CH 2 ; 
 n is 0 or 1; 
 R a , R b  are independently of one another selected from optionally substituted C 1 -C 6 -alkyl, C 2 -C 6 -alkyenyl, C 2 -C 6 -alkynyl, C 3 -C 6 -cycloalkyl, C 4 -C 10 -bicycloalkyl, and C 6 -C 10 -tricycloalkyl, where the last three groups mentioned may optionally be substituted by halogen or C 1 -C 4 -alkyl, or halogen, CN, OR 1 , NR 2 R 3 , NO 2 , SR 4 , SO 2 R 5 , CONR 2 R 3 , SO 2 NR 2 R 3 , COOR 5 , COR 6 , O—COR 6 , 5- or 6-membered heterocyclyl having 1, 2 or 3 heteroatoms selected from O, S, and N, and phenyl, where phenyl and heterocyclyl may optionally have 1, 2 or 3 substituents which are selected independently of one another from C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, NR 2 R 3 , CN, C 1 -C 2 -fluoroalkyl and halogen; 
 R c  is C 1 -C 4 -alkyl; 
 R d , R e  are independently of one another selected from hydrogen, halogen, optionally substituted C 1 -C 6 -alkyl, C 3 -C 6 -cycloalkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, C 1 -C 6 -alkoxy, C 3 -C 6 -cycloalkyloxy, C 3 -C 6 -cycloalkyl-C 1 -C 4 -alkyloxy and optionally substituted phenyl, where CR d R e  may together be CO═O, and the radicals R d , R e  may together form a chain X′-Alk-X″ in which X and X″ are independently of one another O or S, and Alk is C 2 -C 4 -alkanediyl which optionally has 1, 2, 3, or 4 alkyl groups or halogen atoms as substituents; 
 R f , R g  are independently of one another hydrogen, halogen, optionally substituted C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, C 3 -C 6 -cycloalkyloxy, C 3 -C 6 -cycloalkyl-C 1 -C 4 -alkyloxy, or C 3 -C 6 -cycloalkyl, or the radicals R f , R g  may together form a chain of X′-Alk-X″ in which Alk, X′, and X″ have the aforementioned meanings; 
 R h , R i  are independently of one another hydrogen, halogen, optionally substituted C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, C 3 -C 6 -cycloalkyloxy, C 3 -C 6 -cycloalkyl-C 1 -C 4 -alkyloxy or C 3 -C 6 -cycloalkyl; 
 R k , R P  are independently of one another hydrogen, C 1 -C 4 -alkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -alkoxyalkyl, C 1 -C 6 -alkylcarbonyl, C 1 -C 6 -alkoxycarbonyl, phenylalkyl, phenylcarbonyl, phenoxycarbonyl, where phenyl in the last three groups mentioned may have 1, 2, or 3 substituents which are selected from C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, NR 2 R 3 , CN, C 1 -C 2 -fluoroalkyl and halogen; 
 R m , R n  are independently of one another hydrogen, halogen, optionally substituted C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, C 3 -C 6 -cycloalkyloxy, C 3 -C 6 -cycloalkyl-C 1 -C 4 -alkyloxy or C 3 -C 6 -cycloalkyl; and 
 in the case where X is CR m R n  or N—R k , one of the radicals R d  or R e  may together with one of the radicals of R m , R n , or R k  also be a π bond; 
 R 1 , R 2 , R 3 , R 4 , R 5 , and R 6  are independently of one another H, optionally substituted C 1 -C 6 -alkyl or optionally substituted phenyl, where R 3  may also be a group COR 7 , where R 7  is hydrogen, optionally substituted C 1 -C 4 -alkyl or optionally substituted phenyl, where R 2  with R 3  may also form together with the nitrogen atom to which they are bonded a 5- or 6-membered, saturated or unsaturated heterocyle which may have a further heteroatom selected from O, S, and NR 8  as ring member, where R 8  is hydrogen or C 1 -C 4 -alkyl, or 
 the physiologically acceptable acid addition salts of this compound. 
 
     
     
       2. The compound of the formula I according to  claim 1 , in which Z together with the C atoms to which it is bonded stands for a fused phenyl ring which may have 1, 2, 3, or 4 of the aforementioned substituents R. 
     
     
       3. The compound of the formula I according to  claim 1 , in which either A is a C═W group or D is C═O. 
     
     
       4. The compound of the formula I according to  claim 1 , in which E is a (CH 2 ) k  group in which k is 3, 4, 5, or 6. 
     
     
       5. The compound of the formula I according to  claim 1 , in which B is a chemical bond. 
     
     
       6. The compound of the formula I according to  claim 1 , in which J is CH 2 —CH 2  and Y is CH 2 . 
     
     
       7. The compound of the formula I according to  claim 1 , in which M is N. 
     
     
       8. The compound of the formula I, according to  claim 1 , in which R a  and R b  are independently of one another C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, C 2 -C 6 -alkenyl, C 3 -C 6 -cycloalkyl, C 1 -C 6 -alkoxy-C 1 -C 4 -alkyl or C 3 -C 6 -cycloalkyl-C 1 -C 4 -alkyl. 
     
     
       9. The compound of the formula I according to  claim 8 , in which R a  is C 1 -C 6 -alkyl, and R b  is selected from C 1 -C 6 -alkyl, C 3 -C 6 -cycloalkyl and C 1 -C 2 -fluoroalkyl. 
     
     
       10. The compound of the formula I according to  claim 1  of the formula Ia, 
       
         
           
           
               
               
           
         
         in which n, X, E, J, M, R, R a , R b , R c  and R d  have the aforementioned meanings, and m is 0, 1, 2, or 3. 
       
     
     
       11. A pharmaceutical composition comprising at least one active ingredient selected from the compounds of the formula I according to  claim 1  and the physiologically tolerated acid addition salts thereof, together with physiologically acceptable carriers and/or excipients. 
     
     
       12. The compound of the formula Ia according to  claim 10 , wherein X is CH 2  and R d  is a hydrogen. 
     
     
       13. The compound of the formula Ia according to  claim 10 , in which E is a (CH 2 ) k  group in which k is 3, 4, 5, or 6. 
     
     
       14. The compound of the formula Ia according to  claim 10 , in which J is CH 2 —CH 2  and Y is CH 2 . 
     
     
       15. The compound of the formula Ia according to  claim 10 , in which M is N. 
     
     
       16. The compound of the formula Ia according to  claim 10 , according to  claim 1 , in which Ra and Rb are independently of one another C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, C 2 -C 6 -alkenyl, C 3 -C 6 -cycloalkyl, C 1 -C 6 -alkoxy-C 1 -C 4 -alkyl or C 3 -C 6 -cycloalkyl-C 1 -C 4 -alkyl. 
     
     
       17. The compound of the formula Ia according to  claim 10 , in which R a  is C 1 -C 6 -alkyl, and R b  is selected from C 1 -C 6 -alkyl, C 3 -C 6 -cycloalkyl and C 1 -C 2 -fluoroalkyl.